Atypical antipsychotic (AA) drugs are widely prescribed to adolescents, adults, and the elderly for schizophrenia, bipolar disorder and dementia. Patients taking AA drugs have increased fracture risk and young adults may have impaired bone accrual, although the mechanisms have not been delineated. Additional side effects include sleep disruption, hyperphagia, hyperglycemia and obesity. Although AA drugs are necessary for the well being of many patients, understanding the mechanisms of their side effects is critical for improving drug design. Risperidone (RIS) is a commonly prescribed AA, and we showed that RIS-treated mice have significant trabecular bone loss due to increased bone resorption and reduced bone formation (uncoupled remodeling). Because AA drugs have complex receptor pharmacology, there are many potential mechanisms for AA-induced bone loss. We demonstrated direct effects of RIS on osteoclasts, and found evidence for centrally-mediated effects of RIS on bone. Moreover we showed that the ?-blocker propranolol blocks RIS-induced bone loss, suggesting sympathetic nervous system (SNS) activation is involved. Another critical observation is the effect of RIS on brown adipose tissue (BAT), the function of which has been associated with bone changes in a variety of models. Interestingly, AA drugs are also known to cause circadian disruption and altered fuel utilization to fatty acid oxidation (fuel switching). My major hypotheses are that RIS acts centrally to disrupt circadian rhythms in the brain and causes fuel switching and BAT activation, which ultimately lead to bone loss and fractures. Understanding how RIS imparts these changes will have a significant impact on bone and metabolic health. To test these tenets I propose two aims: Specific Aim 1. Test the hypothesis that RIS acts centrally to disrupt the circadian rhythm of bone. Regions of the brain that bind RIS and also connect to the innervation of bone are unknown. We will perform neuron tracing from bone to brain, coupled with RIS binding assays to identify candidate regions of the brain that are targeted by RIS and also innervate bone. RIS will then be administered through intracerebroventricular injection or oral gavage and target gene expression analyzed in the brain and bone. Specific Aim 2. Test the role of RIS-induced fuel switching and BAT activation in mediating trabecular bone loss. RIS causes fuel switching to fatty acid oxidation, which is required for maintaining normal body temperature. We hypothesize that bone loss from RIS is due to sympathetic drive for thermogenesis. However, an indirect effect of BAT on bone may also uncouple remodeling. We will test this using denervation and a selective ?3-adreneric receptor inhibitor to block BAT thermogenesis after RIS treatment. The proposed work will broaden our understanding of the adipose-neural-bone network and impact the health of patients treated with AA drugs.